The Neurocritic

Sunday, April 26, 2015

The U.S. Food and Drug Administration recently admonished TauMark™, a brain diagnostics company, for advertising brain scans that can diagnose chronic traumatic encephalopathy (CTE), Alzheimer's disease, and other types of dementia. The Los Angeles Times reported that the FDA ordered UCLA researcher Dr. Gary Small and his colleague/business partner Dr. Jorge Barrio to remove misleading information from their company website (example shown below).

The website suggests in a promotional context that FDDNP, an investigational new drug, is safe and effective for the purpose for which it is being investigated or otherwise promotes the drug. As a result, FDDNP is misbranded under section 502(f)(1) of the FD&C Act...

[18F]-FDDNP1 is a molecular imaging probe that crosses the blood brain barrier and binds to several kinds of abnormal proteins in the brain. When tagged with a radioactive tracer, FDDNP can be visualized using PET (positron emission tomography).

Despite what the name of the company implies, FDDNP is not an exclusive tau marker. FDDNP may bind to tau protein[although this is disputed],2 but it also binds to beta-amyloid, found in the clumpy plaques that form in the brains of those with Alzheimer's disease. Tau is found in neurofibrillary tangles, also characteristic of Alzheimer's pathology, and seen in other neurodegenerative tauopathies such as CTE.

The big deal with this and other radiotracers is that the pathological proteins can now be visualized in living human beings. Previously, an Alzheimer's diagnosis could only be given at autopsy, when the post-mortem brain tissue was processed to reveal plaques and tangles. So PET imaging is a BIG improvement. But still, a scan alone is not completely diagnostic, as noted by the Alzheimer's Association:

Even though amyloid plaques in the brain are a characteristic feature of Alzheimer's disease, their presence cannot be used to diagnose the disease. Many people have amyloid plaques in the brain but have no symptoms of cognitive decline or Alzheimer's disease. Because amyloid plaques cannot be used to diagnose Alzheimer's disease, amyloid imaging is not recommended for routine use in patients suspected of having Alzheimer's disease.

There are currently three FDA-approved molecular tracers that bind to beta-amyloid: florbetapir, flutemetamol, and florbetaben (note that none of these is FDDNP). But the big selling point of TauMark™ is (of course) the tau marker part, which would also label tau in the brains of individuals with CTE and frontotemporal dementia, diseases not characterized by amyloid plaques. But how can you tell the difference, when FDDNP targets plaques and tangles (and prion proteins, for that matter)?

A new study by the UCLA team demonstrated that the distribution of FDDNP labeling in the brains of Alzheimer's patients differs from that seen in a selected group of former NFL players with cognitive complaints (Barrio et al., 2015). These retired athletes (and others with a history of multiple concussions) are at risk of developing the brain pathology known as chronic traumatic encephalopathy.

It's a well-established fact that brains with Alzheimer's disease, frontotemporal lobar degeneration, or Lou Gehrig's disease (for example) all show different patterns of neurodegeneration, so why not extend this to CTE? This may seem like a reasonable approach, but there are problems with some of the assumptions.

Perhaps the most deceptive claim is that “TauMark owns the exclusive license of the first and only brain measure of tau protein...” Au contraire! A review of recent developments in tau PET imaging (Zimmer et al., 2014) said that...

...six novel tau imaging agents—[18F]THK523, [18F]THK5105, [18F]THK5117, [18F]T807, [18F]T808, and [11C]PBB3—have been described and are considered promising as potential tau radioligands.

Note that [18F]FDDNP is not among the six.2,3 In fact, Zimmer et al. (2014) mentioned that in brain slices, “[3H]FDDNP failed to demonstrate overt labeling of tau pathology.” 2

So to recap, the FDA considered TauMark marketing to be “concerning from a public health perspective.” Their letter warned:

Your website describes FDDNP for use in brain PET scans to diagnose traumatic brain injuries, Alzheimer’s disease, and other neurological conditions. These uses are ones for which a prescription would be needed because they require the supervision of a physician and adequate directions for lay use cannot be written.

At this point, astute followers of The Neurocritic and Neurobollocks might ask, “Hey, how does Dr. Daniel Amen get away with claiming that his SPECT scans can accurately diagnose different types of dementia, each with different ‘treatment plans’?”

1FDDNP is 2-(1-(6-[(2-[(18)F]fluoroethyl)(methyl)amino]-2-naphthyl)ethylidene)malononitrile.

2 Or what is presumed to be tau. FDDNP is supposedly a tracer for both tau and amyloid, but some experts think it's neither. Zimmer et al. (2014) stated:

Though ... [18F]FDDNP appeared to bind both amyloid plaques and tau tangles, a subsequent study using [3H]FDDNP autoradiography in sections containing neurofibrillary tangles (NFTs) failed to demonstrate overt labeling of tau pathology because of a low affinity for NFTs.

3James et al. (2015) were more generous in their review of tau PET imaging, mentioning the existence of seven tau tracers (including FDDNP). But again they noted the lack of specificity. (Parenthetically speaking, [18F]T807 imaging has been done in a single NFL player, which may be of interest in a future post.)

Wednesday, April 15, 2015

What are the Hot Topics in cognitive neuroscience? We could ask these people, or we could take a more populist approach by looking at conference abstracts. I consulted the program for the recent Cognitive Neuroscience Society meeting (CNS 2015) and made a word cloud using Wordle.1 For comparison, we'll examine the program for the most recent Computational and Systems Neuroscience meeting (Cosyne 2015).

Monday, April 06, 2015

What can we do to solve the mind/body problem once and for all? How do we cure devastating brain diseases like Alzheimer's, Parkinson's, schizophrenia, and depression? I am steadfast in following the course of my 500 year plan that may eventually solve these pressing issues, to the benefit of all Americans!

There's nothing like attending a conference in the midst of a serious family illness to make one take stock of what's important. My mind/brain has been elsewhere lately, along with my body in a different location. My blogging output has declined while I live in this alternate reality. But aside from the disunion caused by depersonalization/derealization, what is my view of the state of Cognitive Neuroscience in 2015?

But first, let's examine what we're trying to unify. Studies of mind and studies of brain? Cognition and neuroscience?Let's start with “neuroscience”.

Neuroscience is the scientific study of the nervous system. Traditionally, neuroscience has been seen as a branch of biology. ... The term neurobiology is usually used interchangeably with the term neuroscience, although the former refers specifically to the biology of the nervous system, whereas the latter refers to the entire science of the nervous system.

This reminds me of a recent post by Neuroskeptic, who asked: Is Neuroscience Based On Biology? On the face of it, this seemed like an absurd question to me, because the brain is a biological organ and of course we must know its biology to understand how it works. But what he really meant was, Is Cognitive Science Based On Biology? I say this because he adopted a functionalist view and used the brain-as-computer metaphor:

Could it be that brains are only accidentally made of cells, just as computers are only accidentally made of semiconductors? If so, neuroscience would not be founded on biology but on something else, something analogous to the mathematical logic that underpins computer science. What could this be?

This view [the brain is just a digital computer and the mind is just a computer program] has the consequence that there’s nothing essentially biological about the human mind. The brain just happens to be one of an indefinitely large number of different kinds of hardware computers that could sustain the programs which make up human intelligence. ... So, for example, if you made a computer out of old beer cans powered by windmills, if it had the right program. It would have to have a mind.

The infamous argument-by-beer-cans. In the end, Neuroskeptic admitted he's not sure he subscribes to this view. But the post sparked an interesting discussion. There were a number of good comments, e.g. Jayarava said: “Neuro-science absolutely needs to be neuron-science, to focus on brains made of cells because that's what we need to understand in the first place.” Indeed, some neuroscientists don't consider “cognitive neuroscience” to be “neuroscience” at all, because the measured units are higher (i.e., less reductionist) than single neurons.1

A comment by Adam Calhoun gets to the heart of the matter, making a sharp point about the disunity of neuroscience:

Although we use the term 'neuroscience' as though it refers to one coherent discipline, the problem here is that it does not. If you were to pick a neuroscientist at random and ask: "what does your field study?" you will not get the same answer two times in a row.

Neural development? Molecular pathways? Cognition? Visual processing? Are these the same field? Or different fields that have been given the same name?

One of the selling points of neuroscience is its interdisciplinary nature, but it's really hard to talk to each other if we don't speak the same language (or work in the same field). Some graduate programs dwell in an idealized world where students can become knowledgeable in molecular, cellular, developmental, systems, and cognitive neuroscience in one year. The reality is that professors in some subfields couldn't pass the exams given in another subfield. And why would they possibly want to do this, given they're way too busy writing grants.

Sometimes I think cognitive neuroscience is on a completely different planet from the other branches, estranged from even its closest cousin, behavioral neuroscience.2 It's even further away these days from systems neuroscience3— which used to be dominated by the glamour of single unit recordings in monkeys, but now is all about manipulating circuits with opto- and chemogenetics.

But as the Systems/Circuits techniques get more and more advanced (and invasive and mechanistic), the gulf between animal and human studies grows larger and the prospects for clinical translation fade. [Until the neuroengineers come in and save the day.]

I'll end on a more optimistic note, with a quote from a man who wished to bridge the gap between Aplysia californica and Sigmund Freud.

2Though if you look at the mission of the journal called Behavioral Neuroscience, its scope has broadened to include just about anything:

We seek empirical papers reporting novel results that provide insight into the mechanisms by which nervous systems produce and are affected by behavior. Experimental subjects may include human and non-human animals and may address any phase of the lifespan, from early development to senescence.

Studies employing brain-imaging techniques in normal and pathological human populations are encouraged, as are studies using non-traditional species (including invertebrates) and employing comparative analyses. Studies using computational approaches to understand behavior and cognition are particularly encouraged.

In addition to behavior, it is expected that some aspect of nervous system function will be manipulated or observed, ranging across molecular, cellular, neuroanatomical, neuroendocrinological, neuropharmacological, and neurophysiological levels of analysis. Behavioral studies are welcome so long as their implications for our understanding of the nervous system are clearly described in the paper.

3 Actually, systems neuroscience is mostly about engineering and computational modelling these days.

Neuroscientists specialize in the study of the brain and the nervous system. They are inspired to try to decipher the brain’s command of all its diverse functions. Over the years, the neuroscience field has made enormous progress. Scientists continue to strive for a deeper understanding of how the brain’s 100 billion nerve cells [NOTE: the number is only 86 billion] are born, grow, and connect. They study how these cells organize themselves into effective, functional circuits that usually remain in working order for life.

SfN advances the understanding of the brain and the nervous system by bringing together scientists of diverse backgrounds, facilitating the integration of research directed at all levels of biological organization, and encouraging translational research and the application of new scientific knowledge to develop improved disease treatments and cures.

“…We should all want a smarter, more effective government. And while we may not be able to bridge our biggest philosophical differences this year, we can make real progress. With or without this Congress, I will keep taking actions that help the economy grow. But I can do a whole lot more with your help. Because when we act together, there is nothing the United States of America can’t achieve.”

About Me

Born in West Virginia in 1980, The Neurocritic embarked upon a roadtrip across America at the age of thirteen with his mother. She abandoned him when they reached San Francisco and The Neurocritic descended into a spiral of drug abuse and prostitution. At fifteen, The Neurocritic's psychiatrist encouraged him to start writing as a form of therapy.